BACKGROUND: Asthma represents a syndrome for which our understanding of the molecular processes underlying discrete sub-diseases (i.e., endotypes), beyond atopic asthma, is limited. The public health needs to characterize etiology-associated endotype risks is becoming urgent. In particular, the roles of polyaromatic hydrocarbon (PAH), globally distributed combustion by-products, toward the two known endotypes - T helper 2 cell high (Th2) or T helper 2 cell low (non-Th2) - warrants clarification. OBJECTIVES: To explain ambient B[a]P association with non-atopic asthma (i.e., a proxy of non-Th2 endotype) is markedly different from that with atopic asthma (i.e., a proxy for Th2-high endotype). METHODS: In a case-control study, we compare the non-atopic as well as atopic asthmatic boys and girls against their respective controls in terms of the ambient Benzo[a]pyrene concentration nearest to their home, plasma 15-Ft2-isoprostane (15-Ft2-isoP), urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), and lung function deficit. We repeated the analysis for i) dichotomous asthma outcome and ii) multinomial asthma-overweight/obese (OV/OB) combined outcomes. RESULTS: The non-atopic asthma cases are associated with a significantly higher median B[a]P (11.16 ng/m3) compared to that in the non-atopic controls (3.83 ng/m3; P-value < 0.001). In asthma-OV/OB stratified analysis, the non-atopic girls with lean and OV/OB asthma are associated with a step-wisely elevated B[a]P (median,11.16 and 18.00 ng/m3, respectively), compared to the non-atopic lean control girls (median, 4.28 ng/m3, P-value < 0.001). In contrast, atopic asthmatic children (2.73 ng/m3) are not associated with a significantly elevated median B[a]P, compared to the atopic control children (2.60 ng/m3; P-value > 0.05). Based on the logistic regression model, on ln-unit increate in B[a]P is associated with 4.7-times greater odds (95% CI, 1.9-11.5, P = 0.001) of asthma among the non-atopic boys. The same unit increase in B[a]P is associated with 44.8-times greater odds (95% CI, 4.7-428.2, P = 0.001) among the non-atopic girls after adjusting for urinary Cotinine, lung function deficit, 15-Ft2-isoP, and 8-oxodG. CONCLUSIONS: Ambient B[a]P is robustly associated with non-atopic asthma, while it has no clear associations with atopic asthma among lean children. Furthermore, lung function deficit, 15-Ft2-isoP, and 8-oxodG are associated with profound alteration of B[a]P-asthma associations among the non-atopic children.

College of Health Lehigh University Bethlehem PA USA

Department of Genetic Toxicology and Nanotoxicology Institute of Experimental Medicine Czech Academy of Sciences Prague Czech Republic

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Ferrante G, La Grutta S, et al. Front. Pediatr. 2018:186. 10.3389/fped.2018.00186. PubMed PMC

Hay SI, Jayaraman SP, Truelsen T, Sorensen RJD, Millear A, Giussani G, et al. GBD 2015 disease and injury incidence and prevalence collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the global burden of disease stud. Lancet. 2017;389:E1–E1. ELSEVIER SCIENCE INC 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA.

Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181:315–23. American Thoracic Society. PubMed PMC

Lötvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127:355–360. doi: 10.1016/j.jaci.2010.11.037. PubMed DOI

Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18:716–725. doi: 10.1038/nm.2678. PubMed DOI

Wenzel S. Severe asthma: from characteristics to phenotypes to endotypes. Clin Exp Allergy. 2012;42:650–8. PubMed

Custovic A, Henderson J, Simpson A. Does understanding endotypes translate to better asthma management options for all? J Allergy Clin Immunol. 2019;144:25–33. Elsevier. PubMed

Nunes C, Pereira AM, Morais-Almeida M. Asthma costs and social impact. Asthma Res Pract. 2017;3:1. doi: 10.1186/s40733-016-0029-3. PubMed DOI PMC

Esteban-Gorgojo I, Antolín-Amérigo D, Domínguez-Ortega J, Quirce S. Non-eosinophilic asthma: current perspectives. J Asthma Allergy. 2018;11:267. doi: 10.2147/JAA.S153097. PubMed DOI PMC

Kuruvilla ME, Lee FE-H, Lee GB. Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clin Rev Allergy Immunol Springer. 2019;56:219–233. doi: 10.1007/s12016-018-8712-1. PubMed DOI PMC

Guibas G V, Mathioudakis AG, Tsoumani M, Tsabouri S. Relationship of allergy with asthma: there are more than the allergy “Eggs” in the asthma “Basket” [Internet]. Front Pediatr. 2017:92. Available from: https://www.frontiersin.org/article/10.3389/fped.2017.00092. PubMed DOI PMC

Zwaigenbaum L, Bryson S, Lord C, Rogers S, Carter A, Carver L, et al. No Title. In: Australian Government, editor. Env Heal Perspect [Internet]. 1995/03/01. Copenhagen: Blackwell Publishing Ltd; 2013;17:n/a-n/a. Available from: http://www.biomedcentral.com/1471-2431/13/124/prepub.

Chung KF. Asthma phenotyping: a necessity for improved therapeutic precision and new targeted therapies. J Intern Med. 2016;279:192–204. Wiley Online Library. PubMed

Agache IO. From phenotypes to endotypes to asthma treatment. Curr Opin Allergy Clin Immunol. 2013;13:249–56. PubMed

McConnell R, Berhane K, Yao L, Jerrett M, Lurmann F, Gilliland F, et al. Traffic, susceptibility, and childhood asthma. Environ Health Perspect National Institute of Environmental Health Sciences. 2006;114:766–772. doi: 10.1289/ehp.8594. PubMed DOI PMC

Fang Z, Huang C, Zhang J, Xie J, Dai S, Ge E, et al. Traffic-related air pollution induces non-allergic eosinophilic airway inflammation and cough hypersensitivity in Guinea-pigs. Clin Exp Allergy. 2019;49:366–377. doi: 10.1111/cea.13308. PubMed DOI

Honkova K, Rossnerova A, Pavlikova J, Svecova V, Klema J, Topinka J, et al. Gene expression profiling in healthy newborns from diverse localities of the Czech Republic. Environ Mol Mutagen. 2018;59:401–15. PubMed

Choi H, Dostal M, Pastorkova A, Rossner P, Jr, Sram RJ, Ho S-M. Greater susceptibility of girls to airborne Benzo [a] pyrene for obesity-associated childhood asthma. Environ Int. Elsevier. 2018;121:308–316. doi: 10.1016/j.envint.2018.08.061. PubMed DOI

Choi H, Song W, Wang M, Sram RJ, Zhang B. Benzo[a]pyrene is associated with dysregulated myelo-lymphoid hematopoiesis in asthmatic children. Environ Int. 2019;128:218–232. doi: 10.1016/j.envint.2019.04.052. PubMed DOI

Fernández D, Sram RJ, Dostal M, Pastorkova A, Gmuender H, Choi H. Modeling unobserved heterogeneity in susceptibility to ambient benzo[a]pyrene concentration among children with allergic asthma using an unsupervised learning algorithm. Int J Environ Res Public Health. 2018;15:106. PubMed PMC

Rossnerova A, Spatova M, Rossner P, Solansky I, Sram RJ. The impact of air pollution on the levels of micronuclei measured by automated image analysis. Mutat res. 2009;669:42–47. doi: 10.1016/j.mrfmmm.2009.04.008. PubMed DOI

Ambroz A, Vlkova V, Rossner P, Rossnerova A, Svecova V, Milcova A, et al. Impact of air pollution on oxidative DNA damage and lipid peroxidation in mothers and their newborns. Int J Hyg Env Heal. 2016;219:545–556. doi: 10.1016/j.ijheh.2016.05.010. PubMed DOI

Choi H, Tabashidze N, Rossner P, Dostal M, Pastorkova A, Kong SW, et al. Altered vulnerability to asthma at various levels of ambient Benzo[a]Pyrene by CTLA4, STAT4 and CYP2E1 polymorphisms. Environ Pollut. 2017;231:1134–44. Elsevier. PubMed

Sram RJ, Binkova B, Dostal M, Merkerova-Dostalova M, Libalova H, Milcova A, et al. Health impact of air pollution to children. Int J Hyg Environ Health Elsevier. 2013;216:533–540. doi: 10.1016/j.ijheh.2012.12.001. PubMed DOI

Choi H, Harrison R, Komulainen H, Saborit JMD. Polycyclic aromatic hydrocarbons. WHO Guidel indoor air Qual Sel Pollut. World Health Organization; 2010.

Pinto JP, Stevens RK, Willis RD, Kellogg R, Mamane Y, Novak J, et al. Czech air quality monitoring and receptor modeling study. Environ Sci Technol. 1998;32:843–854. doi: 10.1021/es970174p. DOI

Ghosh R, Rossner P, Honkova K, Dostal M, Sram RJ, Hertz-Picciotto I. Air pollution and childhood bronchitis: interaction with xenobiotic, immune regulatory and DNA repair genes. Environ Int. 2016;87:94–100. doi: 10.1016/j.envint.2015.10.002. PubMed DOI

Hertz-Picciotto I, Baker RJ, Yap P-S, Dostál M, Joad JP, Lipsett M, et al. Early childhood lower respiratory illness and air pollution. Environ Health Perspect. National Institute of Environmental Health Science. 2007;115:1510. PubMed PMC

Rossner P, Jr, Rossnerova A, Spatova M, Beskid O, Uhlirova K, Libalova H, et al. Analysis of biomarkers in a Czech population exposed to heavy air pollution. Part II: chromosomal aberrations and oxidative stress. Mutagenesis. 2012;28:97–106. doi: 10.1093/mutage/ges058. PubMed DOI

Rossner P, Svecova V, Schmuczerova J, Milcova A, Tabashidze N, Topinka J, et al. Analysis of biomarkers in a Czech population exposed to heavy air pollution. Part I: bulky DNA adducts. Mutagenesis. 2013;28:89–95. doi: 10.1093/mutage/ges057. PubMed DOI

Levy ML, Quanjer PH, Rachel B, Cooper BG, Holmes S, Small IR. Diagnostic Spirometry in Primary Care: Proposed standards for general practice compliant with American Thoracic Society and European Respiratory Society recommendations. Prim Care Respir J. 2009;18:130–47. Nature Publishing Group. PubMed PMC

Butler AR. The Jaffé reaction. Identification of the coloured species. Clin Chim Acta. 1975;59:227–232. doi: 10.1016/0009-8981(75)90033-9. PubMed DOI

Rossnerova A, Spatova M, Rossner P, Novakova Z, Solansky I, Sram RJ. Factors affecting the frequency of micronuclei in asthmatic and healthy children from Ostrava. Mutat Res Mol Mech Mutagen. 2011;708:44–49. doi: 10.1016/j.mrfmmm.2011.01.004. PubMed DOI

Dostál M, Milcová A, Binková B, Kotěšovec F, Nožička J, Topinka J, et al. Environmental tobacco smoke exposure in children in two districts of the Czech Republic. Int J Hyg Env Heal. 2008;211:318–325. doi: 10.1016/j.ijheh.2007.07.001. PubMed DOI

Ghosh R, Topinka J, Joad JP, Dostal M, Sram RJ, Hertz-Picciotto I. Air pollutants, genes and early childhood acute bronchitis. Mutat Res Mol Mech Mutagen. 2013;749:80–6. PubMed

Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey. Bmj. 2000;320:1240. doi: 10.1136/bmj.320.7244.1240. PubMed DOI PMC

de Nijs SB, Venekamp LN, Bel EH. Adult-onset asthma: is it really different? Eur Respir Rev Eur Respiratory Soc. 2013;22:44–52. doi: 10.1183/09059180.00007112. PubMed DOI PMC

Li N, Buglak N. Convergence of air pollutant-induced redox-sensitive signals in the dendritic cells contributes to asthma pathogenesis. Toxicol Lett [Internet] 2015;237:55–60. doi: 10.1016/j.toxlet.2015.05.017. PubMed DOI

Li N, Sioutas C, Cho A, Schmitz D, Misra C, Sempf J, et al. Ultrafine particulate pollutants induce oxidative stress and mitochondrial damage. Env Heal Perspect. 2003;111:455–460. doi: 10.1289/ehp.6000. PubMed DOI PMC

Papadopoulos NG, Arakawa H, Carlsen K, Custovic A, Gern J, Lemanske R, et al. International consensus on (ICON) pediatric asthma. Allergy. 2012;67:976–97. Wiley Online Library. PubMed PMC

Leone N, Courbon D, Thomas F, Bean K, Jégo B, Leynaert B, et al. Lung function impairment and metabolic syndrome: the critical role of abdominal obesity. Am J Respir Crit Care Med. 2009;179:509–16. American Thoracic Society. PubMed

Guarnieri M, Balmes JR. Outdoor air pollution and asthma. Lancet. 2014;383:1581–1592. doi: 10.1016/S0140-6736(14)60617-6. PubMed DOI PMC

Baldacci S, Maio S, Cerrai S, Sarno G, Baïz N, Simoni M, et al. Allergy and asthma: effects of the exposure to particulate matter and biological allergens. Respir Med Elsevier. 2015;109:1089–1104. doi: 10.1016/j.rmed.2015.05.017. PubMed DOI

Manners S, Alam R, Schwartz DA, Gorska MM. A mouse model links asthma susceptibility to prenatal exposure to diesel exhaust. J Allergy Clin Immunol. 2014;134:63–72. doi: 10.1016/j.jaci.2013.10.047. PubMed DOI PMC

Perzanowski MS, Chew GL, Divjan A, Jung KH, Ridder R, Tang D, et al. Early-life cockroach allergen and polycyclic aromatic hydrocarbon exposures predict cockroach sensitization among inner-city children. J Allergy Clin Immunol. 2013;131:886–893. doi: 10.1016/j.jaci.2012.12.666. PubMed DOI PMC

Hew KM, Walker AI, Kohli A, Garcia M, Syed A, McDonald-Hyman C, et al. Childhood exposure to ambient polycyclic aromatic hydrocarbons is linked to epigenetic modifications and impaired systemic immunity in T cells. Clin Exp Allergy. 2015;45:238–248. doi: 10.1111/cea.12377. PubMed DOI PMC

Li N, Georas S, Alexis N, Fritz P, Xia T, Williams MA, et al. A work group report on ultrafine particles (American Academy of Allergy, Asthma & Immunology): why ambient ultrafine and engineered nanoparticles should receive special attention for possible adverse health outcomes in human subjects. J Allergy Clin Immunol Elsevier. 2016;138:386–396. doi: 10.1016/j.jaci.2016.02.023. PubMed DOI PMC

Binkova B, Topinka J, Sram RJ, Sevastyanova O, Novakova Z, Schmuczerova J, et al. In vitro genotoxicity of PAH mixtures and organic extract from urban air particles part I: acellular assay. Mutat Res [Internet] 2007;620:114–122. doi: 10.1016/j.mrfmmm.2007.03.001. PubMed DOI

van Grevenynghe J, Bernard M, Langouet S, Le Berre C, Fest T, Fardel O. Human CD34-positive hematopoietic stem cells constitute targets for carcinogenic polycyclic aromatic hydrocarbons. J Pharmacol Exp Ther. 2005;314:693–702. doi: 10.1124/jpet.105.084780. PubMed DOI

Choi H, Spengler J. Source attribution of personal exposure to airborne polycyclic aromatic hydrocarbon mixture using concurrent personal, indoor, and outdoor measurements. Environ Int. 2014;63:173–181. doi: 10.1016/j.envint.2013.11.007. PubMed DOI PMC

Choi H, Melly S, Spengler J. Intraurban and longitudinal variability of classical pollutants in Kraków, Poland, 2000-2010. Int J Environ Res Public Health. 2015;12:4967–4991. doi: 10.3390/ijerph120504967. PubMed DOI PMC

Choi H, Zdeb M, Perera F, Spengler J. Estimation of chronic personal exposure to airborne polycyclic aromatic hydrocarbons. Sci Total Environ. 2015;527–528:252–261. doi: 10.1016/j.scitotenv.2015.04.085. PubMed DOI PMC

Choi H, Wang L, Lin X, Spengler JD, Perera FP. Fetal window of vulnerability to airborne polycyclic aromatic hydrocarbons on proportional intrauterine growth restriction. PLoS One. 2012;7. PubMed PMC

Pulkrabova J, Stupak M, Svarcova A, Rossner P, Rossnerova A, Ambroz A, et al. Relationship between atmospheric pollution in the residential area and concentrations of polycyclic aromatic hydrocarbons (PAHs) in human breast milk. Sci Total Environ. 2016;562:640–647. doi: 10.1016/j.scitotenv.2016.04.013. PubMed DOI

See more in PubMed

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